Intervertebral disc degeneration (IDD) contributes to many spinal disorders such as chronic disabling low back pain, disc herniation, spinal stenosis and vertebral instability. IDD-associated back pain is the leading source of disability in people 45 years of age or younger, resulting in national economic losses estimated at more than 90 billion dollars a year in the United State alone. IDD is correlated with many diverse pathophysiologic etiologies, including genetics, smoking, mechanical injury, aging and other environmental factors, with aging being an inevitable and key contributor of IDD. Oxidative stress and genotoxic stress are widely accepted to contribute to aging in general10. However, whether oxidative or genotoxic stress are also a key culprits in disc aging has not been adequately explored due to a lack of a good animal model of age-related IDD. We recently demonstrated that a mouse model of accelerated aging (Ercc1-/ mice) caused by reduced expression of the DNA repair endonuclease ERCC1-XPF displays considerable disc matrix proteoglycan (PG) loss, a universal hallmark of disc aging, by five months of age. This leads us to hypothesize that accumulation of endogenous DNA damage plays a causal role in disc aging and PG loss. To test this hypothesis, two aims are proposed: (1) to determine if IDD is due to oxidative/genotoxic stress-induced disc cell senescence and death and loss of cell function, and (2) to determine if oxidative/genotoxic stress induces disc matrix PG degradation. The successful completion of these experiments will determine if there is a causal relationship between oxidative DNA damage and age- associated IDD and yield novel insights into the molecular causes of disc PG loss that will be useful for development of rational therapeutic interventions to prevent or delay IDD. PUBLIC HEALTH RELEVANCE: These studies aim at understanding how aging intervertebral discs lose important matrix structural constituents in order to develop rational and effective treatment of spinal disorders such as chronic disabling low back pain.